Rosacea, originally termed acne rosacea, is a chronic inflammatory skin condition primarily affecting the areas of the eyelids, chin, nose, cheeks, and forehead of adults. The condition is characterized by erythema (redness), papules, rhinophyma, telagiectasia, prominent vascularization, dryness, pustules, swelling, lesions, inflammation, infection, enlarged nasal area, hypertrophy of the sebaceous glands, and nodules either singly or in combination in the involved skin areas, primarily in the central areas of the face. Some of these clinical signs, in particular the erythema, are thought to be caused by the dilation of blood vessels. Rosacea may further be characterized by flushing and blushing. In rare instances, rosacea may also occur on the trunk and extremities, such as the chest, neck, back, or scalp.
Eyelids affected by rosacea may be manifested by mild conjunctival irritation or inflammation of the meibomian (oil) glands on the eyelid margin. Chronic eyelid irritation can result in loss of eyelashes. No visual impairment accompanies the eyelid irritation.
Rosacea, in mild form, brings about a slight flushing of the nose and cheeks and, in some cases, the forehead and chin. However, in a severe form, lesions appear which are deep or purplish red and which include a chronic dilation of the superficial capillaries, i.e. telangiectasia. Also, in severe form, inflammatory acneiform pustules are present. Chronic involvement of the nose with rosacea in men can cause a bulbous enlargement known as rhinophyma. However, women are twice as likely as men to have rosacea. In women, this rhinophyma often takes the form of pimples and redness of or near the nose. Similarly, women are three times more likely than men to exhibit symptoms of perioral dermatitis, where redness and a rash appear above the upper lip attaching into the nose.
Another acute form of rosacea is known as granulomatous rosacea and, as such, is considered to be a distinctive form of the papular aspect of the disease. Therein, discreet pustules appear as yellowish brown nodules and as epithelioid cell granulomatous.
Rosacea may be diagnosed based on the presence of one or more of its manifestations. Patients with rosacea may have different triggering factors for the manifestations. These triggering factors may include, for example, any of genetic disposition, gastrointestinal disturbances (including dyspepsia with gastric hypochlorhydia and infestation with microaerophilic gram-negative bacteria Helicobacter pylori), hypertension, Demodex folliculorum mites, psychogenic factors, spicy foods, blushing, flushing, ultraviolet radiation, wind exposure, and stress. Often patients with rosacea are particularly susceptible to blushing and flushing, and signs of this may be an indicator of the probability of rosacea suffering later in life.
There are typically four stages of rosacea, as well as a predisposition to the condition. The stages can be defined as follows:                Pre-rosacea: skin flushes easily and redness lasts longer than normal and there is a family history of the condition.        Stage I: Frequent flushing, some persistent erythema.        Stage II: Persistent erythema and telangiectasias.        Stage III: Papules and pustules (plus Stage II).        Stage IV: Rhinophyma (bumpy, bulbous nose).        
While certain lesions of rosacea may mimic lesions of acne vulgaris, the processes are separate and distinct. The principal differences between the two skin conditions are the presence of comedones (whiteheads and blackheads) in acne vulgaris only and not in rosacea, the characteristic mid-facial localization and flushing of rosacea not seen in acne, and the potential for eyelid involvement in rosacea which never occurs in acne. In fact, the clinical observation has been made that people who have classic acne vulgaris as teenagers rarely, if ever, develop full-blown rosacea as adults.
In the classic situation, rosacea is most common in adults between the ages of 20 and 84. For example, 63% of those people suffering from rosacea are between the ages of 20 and 59, while 27% of those people suffering from rosacea are between the ages of 60 and 84.
A further age breakdown shows that 19.1% of people suffering from rosacea are between the ages of 20 and 39; 47.4% are between the ages of 40 and 59; and 27.4% are between the ages of 60 and 84. Accordingly, the majority of rosacea sufferers have an age of at least 40 years.
The underlying cause of rosacea is unknown and has been a frequently discussed medical topic, with little consensus having ever been reached. Dietary influence, gastrointestinal disturbances, psychologic or hormonal imbalance, sebaceous gland abnormalities, and infection have all been considered but not validated as causes for rosacea. Other theories range from solar-induced dermal connective tissue damage, with resultant vascular distension, to humorally mediated active vasodilatory changes. A causative role has also been suggested for the hair follicle mite, Demodex, C. E. Bonnard, et al., The Demodex Mite Population, J. Amer. Acad. Dermatology, Vol. 28, No. 3, pp. 443-447, March 1993. After much discussion, at least four factors or co-factors have been suggested as the most likely causes of rosacea.
The first of these factors is endocrine related, as rosacea tends to occur most frequently in women. As such, one definite type of rosacea is believed to have a hormonal basis.
A second suggested factor is vasomotor lability, believed to have some connection with menopause, which brings about an impairment of normal or consistent flow of blood to the face and its capillaries. Excessive flow of blood to the face, i.e., the well-known “hot flashes” of menopause, is believed to constitute a factor in the disease and its pathogenesis. More particularly, it has been proven that increased skin temperature, as occurs in facial flushing, increases susceptibility to the condition.
The prominent presence of erythema (redness) and flushing of the face of affected persons with aggravation from heat, sunshine (particularly due to UV light), cold, chemical irritation, emotions, spices, coffee, tea, and alcohol, particularly in persons with a fair complexion, has focused attention on this vasomotor aspect of the disease. However, treatment with medications to block such vasomotor flushing has often had no effect on other aspects of the disease, such as papules and pustules. Further, rosacea-afflicted skin is abnormally sensitive to chemical and physical insults, while the frequent flushing and blushing in rosacea eventually leads to permanent skin redness.
As a third suggested factor, rosacea has been observed as a side effect or immune response to the use of certain cortisone products or standard acne medications, which can bring about a severe form of the condition. When topically applied to rosacea-affected skin, these medications generally irritate the skin and induce rosacea flare-ups. Similarly, agents that dilate blood vessels when ingested, for instance, ethanol and certain medications for high blood pressure, can bring on a rosacea blush when ingested by a person affected with rosacea. However, if untreated, rosacea can result in swollen veins, scattered lumps, and clusters of pustules on the face.
Finally, pathology analysis of the expressed contents of inflamed pustule follicles of the nose in acute rosacea has demonstrated the existence of demodices, which is a signature of the ectoparasite Demodex folliculorum. Accordingly, in such cases, a specific external pathogenic factor is evident. This factor is not present in acne.
Many skin disorders are treated with a single course of therapy on the premise that the etiology and presented symptoms are the result of a single cause. Unfortunately, many diseases, especially skin diseases, are complicated in that the symptoms may be the result of changes in internal, external, or a combination of both environments. Acne and rosacea have previously been identified as resulting from at least two of these conditions. As a result, conventional single agent therapies have been shown not to yield the desired clinical results in treating these diseases, such as, for example, cosmetic improvement (appearance), elimination of pathogenic organisms, reduction of swelling, etc.
Dietary avoidance of spicy foods and alcohol which cause flushing have in the past provided at most temporary symptomatic relief from rosacea. Jansen and Plewig, “Rosacea”, Clinical Dermatology (Philadelphia: Lippincott-Raven Publishers, 1997; chapter 10-7) provide an excellent review of various treatments for rosacea in this regard.
Several potential treatments for rosacea have been disclosed in the art. However, none of these treatments have proven to be particularly effective. For example, U.S. Pat. No. 5,654,013 discloses a method of reducing inflammation in rosacea involving lightly rubbing a block of crystalline sodium chloride over moistened skin in affected areas. No claim was made for any antibiotic effect on bacteria or ectoparasites in the skin.
U.S. Pat. No. 3,867,522 similarly discloses the abrasive use of sodium chloride crystals rubbed over affected skin in acne and related disorders, again with no intended antibiotic effect and with the goal of treatment being the lessening of the severity of the disease and not a permanent or even a temporary cure.
Rosacea has also previously been treated with oral and/or topical antibacterial agents. The oral antibiotics used include tetracycline, erythromycin, and minocycline. This antibiotic treatment has been shown to effectively block progression of rosacea through a poorly-understood anti-inflammatory mechanism, but studies have shown that these medications do not act by killing either bacteria or Demodex folliculorum organisms in affected skin.
One particular antibiotic disclosed in U.S. Pat. No. 5,952,372 as effective for the oral treatment of rosacea is ivermectin (22,23-dihydroavermectin B1). However, it is uncertain whether ivermectin is orally effective in killing Demodex folliculorum, as the patent alleges.
Azoles, e.g. metronidazole and imidazoles, have also been previously used as treatments for rosacea, particularly for moderate to severe rosacea.
However, some patients suffering from rosacea have experienced adverse reactions to, or gain limited relief from, metronidazole containing compositions. Accordingly, compositions demonstrated to have a greater efficacy in treating rosacea than the currently available metronidazole compositions are still needed to provide greater, longer lasting, or more rapid relief to those suffering from this rosacea. However, such alternative compositions have not yet been recognized as more effective in treating rosacea than metronidazole containing compositions to date.
Sodium sulfacetamide with and without sulfur has been utilized for many years to treat acne. A nominal treatment concentration for sodium sulfacetamide is 10% and for sulfur is 5%. SULFACET R® (Dermik Laboratories, Inc. of Fort Washington, Pa.) is a marketed example of such products. However, such treatments have previously not been recognized as effective as compositions containing metronidazole for the treatment of rosacea.
Sulfur alone has been used to treat skin diseases, such as acne, for over 100 years. Sulfur products have been used at levels up to 10% to treat acne. Sulfur has also been combined with resorcinol to improve its performance. Again, however, sulfur alone has not previously been recognized as effective for treating rosacea.
In addition to such pharmaceutical treatments, limiting sun exposure has been suggested as an alternative, or combined, means for managing certain dermatological conditions. For example, A. P. Kelly (Principles and Practice of Dermatology, Sams and Lynch editors, 1990, p. 789) indicates that avoidance of sun exposure is a mechanism to be explored in the management of the skin flushing often seen with rosacea. Similarly, J. K. Wilkins stated (Id., p. 495) that “the degree to which reddening occurs results not only from the intensity of the flushing reaction, but also from the pigmentation of the subject and the visibility of the vessels, which may be enhanced in a sun-damaged dystrophic dermis.” Accordingly, treatment regimens that in some way limit the exposure of skin to sunlight represent other possible alternatives for treating rosacea.
Sunscreens, for example, are designed to protect against sunburn caused by UVB rays, but generally provide little protection against UVA rays. UVA rays are linked to aging and generally have a depressing effect on the immune system and therefore may lead to other dermatological problems such as rosacea. In addition to preventing damage from exposure to UV radiation, the use of such UV absorbers to counteract the sensitizing effects of some dermatological therapeutics has been described in the art. For example, the use of UV absorbers in combination with erythromycin for the treatment of acne is described in U.S. Pat. No. 5,017,366.
There has been great difficulty in the art in preparing antibacterial compositions that can effectively be administered for treating skin diseases. For example, many of the presently known antibacterial compositions for dermatological treatment must remain stable for long periods of time (useful shelf life), not lose their potency (a known characteristic of antibiotics under certain conditions), not form insoluble substances or complexes because of the combining sulfacetamide and other active ingredients, and must minimize irritation to the skin. There is a lack of such antibacterial compositions in the art.
Accordingly, there remains a need in the art for stable topical compositions having a greater effectiveness in treating rosacea than the presently known compositions, such as the metronidazole containing compositions. The present subject matter addresses this need.